The present invention relates to novel agents such as peptides useful in the treatment of neurodegenerative disorders.
Parkinson's disease (PD) is a multifactorial disease caused by both genetic and environmental factors. Although most patients suffering from PD have a sporadic disease, several genetic causes have been identified in recent years. An increasing number of genes that cause inherited forms of PD have provided the opportunity for new insights into the mechanisms at the basis of the disease. These genes include alpha-synuclein, parkin, PINK1, dardarin (LRRK2), and DJ-1.
DJ-1 deletions and point mutations have been found worldwide, and loss of functional protein was shown to cause autosomal recessive PD. DJ-1 encodes a small 189 amino acid protein that is ubiquitously expressed and highly conserved throughout diverse species. DJ-1 is widely distributed and is highly expressed in the brain and extra cerebral tissues. The high expression of DJ-1 in the central nervous system (CNS) is not confined to a single anatomical or functional system. Within the substantia nigra, however, DJ-1 is localized in both neuronal and glial cells, suggesting a distinct role in this area.
Accumulating data suggests that DJ-1 plays an important role in the oxidative stress response, but the exact mechanism of action is unknown [Kim, 2005, Proc. Natl. Acad. Sci. USA. 102, 5215-5220; Choi, 2006, J. Biol. Chem. 281, 10816-10824]. DJ-1 has several isoforms with different isoelectric points (pl). This pl shift is caused by the oxidation of cysteine and methionine residues in DJ-1. Post-mortem studies of brain samples taken from PD patients found that the acidic isoforms of DJ-1 are more abundant in PD brains as compared to controls [Choi, 2006, J. Biol. Chem. 281, 10816-10824]. Elevated levels of DJ-1 were recently reported in the cerebrospinal fluid (CSF) of sporadic PD patients [Waragai, 2006, Biochem. Biophys. Res. Commun. 345, 967-972]. These studies imply that DJ-1 has a role not only in selective inherited cases but also in the more common sporadic disease.
Dopamine is a highly toxic molecule. Neurotoxicity due to elevated cytosolic dopamine has long been implicated in etiology of neurodegeneration in PD. Dopaminergic neurons protect themselves from dopamine toxicity by its concentration within intracytoplasmic vesicles. Vesicular monoamine transporters (VMATs) mediate accumulation of monoamines such as serotonin, dopamine, adrenaline, noradrenaline, and histamine from the cytoplasm into storage organelles. There are two isoforms of VMATs identified in humans: VMAT1 and VMAT2, which are also members of the solute carrier family 18 (SLC18A1 and SLC18A2, respectively). These proteins share 60% sequence identity; however, they demonstrate a range of differences in their physiologic and pharmacologic properties. VMAT1 is expressed primarily in neuroendocrine cells such as the adrenal medulla and pineal gland, while VMAT2 is expressed in all aminergic neurons in the mammalian CNS. The vesicular monoamine transporter-2 (VMAT2) transfers dopamine from the cytoplasm into these synaptic vesicles, thereby controlling intraneuronal sequestration of dopamine, preventing its cytoplasmic oxidation and preparing it for the exocytotic quantal release.
Biogenic amines play critical roles in consciousness, mood, thought, motivation, cognition, perception, and autonomic responses. Alterations in genes encoding VMATs might play an important role in the pathogenesis of neuropsychiatric diseases including bipolar disease, depression, addiction and schizophrenia (Richards, 2006). VMAT2 is a site of action of important drugs such as reserpine and tetrabenazine, both of which inhibit vesicular amine transport. Reserpine is a useful drug in the treatment of hypertension and schizophrenia; however, high dosages of reserpine frequently produce a syndrome resembling depressive disorder. The monoamine theory is one of the major hypotheses about the biological etiology of major depressive disorders. Recent pharmacological and postmortem investigations suggest that depressed patients have alterations in function of serotonergic neuronal system. Elevated levels of VMAT2 have been reported in the brain of bipolar disorder patients and in platelet of untreated depressed patients. It is speculated that altered VMAT2 expression in depressed patients results from a compensatory mechanism to overcome a monoaminergic deficit. Several lines of evidence suggest the involvement of the VMAT in the psychostimulant action of amphetamines which induce monoamine efflux from vesicles.
U.S. Pat. Appl. No. 20060153807 teaches administration of DJ-1 and peptides thereof for the treatment of neurodegenerative diseases such as Parkinson's.